chr19-11058304-A-C

Position:

• chr19-11058304-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003072.5(SMARCA4):​c.4474A>C​(p.Lys1492Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_003072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

SMARCA4 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA4. . Gene score misZ 6.8459 (greater than the threshold 3.09). Trascript score misZ 8.7957 (greater than threshold 3.09). GenCC has associacion of gene with uterine corpus sarcoma, Coffin-Siris syndrome 1, intellectual disability, autosomal dominant 16, rhabdoid tumor predisposition syndrome 2, familial rhabdoid tumor, hereditary nonpolyposis colon cancer, Coffin-Siris syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA4	NM_001387283.1	c.4570A>C	p.Lys1524Gln	missense_variant	32/36	ENST00000646693.2	NP_001374212.1
SMARCA4	NM_003072.5	c.4474A>C	p.Lys1492Gln	missense_variant	31/35	ENST00000344626.10	NP_003063.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA4	ENST00000646693.2	c.4570A>C	p.Lys1524Gln	missense_variant	32/36		NM_001387283.1	ENSP00000495368.1
SMARCA4	ENST00000344626.10	c.4474A>C	p.Lys1492Gln	missense_variant	31/35	1	NM_003072.5	ENSP00000343896.4
SMARCA4	ENST00000643549.1	c.4480A>C	p.Lys1494Gln	missense_variant	31/35			ENSP00000493975.1
SMARCA4	ENST00000541122.6	c.4384A>C	p.Lys1462Gln	missense_variant	31/35	5		ENSP00000445036.2
SMARCA4	ENST00000643296.1	c.4384A>C	p.Lys1462Gln	missense_variant	30/34			ENSP00000496635.1
SMARCA4	ENST00000644737.1	c.4384A>C	p.Lys1462Gln	missense_variant	30/34			ENSP00000495548.1
SMARCA4	ENST00000589677.5	c.4381A>C	p.Lys1461Gln	missense_variant	31/35	5		ENSP00000464778.1
SMARCA4	ENST00000643995.1	c.3895A>C	p.Lys1299Gln	missense_variant	28/32			ENSP00000496004.1
SMARCA4	ENST00000644963.1	c.3124A>C	p.Lys1042Gln	missense_variant	24/28			ENSP00000495599.1
SMARCA4	ENST00000644065.1	c.3106A>C	p.Lys1036Gln	missense_variant	23/27			ENSP00000493615.1
SMARCA4	ENST00000642350.1	c.2968A>C	p.Lys990Gln	missense_variant	23/27			ENSP00000495355.1
SMARCA4	ENST00000643857.1	c.2836A>C	p.Lys946Gln	missense_variant	22/25			ENSP00000494159.1
SMARCA4	ENST00000538456.4	c.640A>C	p.Lys214Gln	missense_variant	5/8	3		ENSP00000495197.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rhabdoid tumor predisposition syndrome 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2020

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMARCA4-related disease. This sequence change replaces lysine with glutamine at codon 1524 of the SMARCA4 protein (p.Lys1524Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;.;T;.;.;.;.;.;.;.;T;.;.;.;.;.;T;T;.;.;.;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.0	M;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;.;.;.;N;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.23
Sift	Benign	0.095	T;.;.;.;.;.;.;.;.;.;T;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Benign	0.17	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T;.;.;.;.;.
Polyphen		0.89	P;.;B;.;.;.;.;.;.;.;P;.;.;.;.;.;.;B;.;.;.;.;.
Vest4		0.72
MutPred		0.52		.;.;Loss of methylation at K1524 (P = 0.0015);.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of methylation at K1524 (P = 0.0015);.;.;.;.;.;
MVP		0.57
MPC		1.8
ClinPred		0.87	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502075; hg19: chr19-11168980;